Synlogic Inc · OTC:SYBX
Synlogic — Investor Presentation (January 2018)
45 slides from Synlogic's investor presentation, Jan 8, 2018
Slide 1: Corporate Overview January 2018: A Novel Class of Living Medicines
Corporate Overview January 2018 A Novel Class of Living Medicines Synthetic BioticTM medicines to perform and deliver critical therapeutic functions to treat diseases throughout the body
Slide 2: Forward Looking Statements
Forward Looking Statements This presentation contains “forward-looking statements” that involve substantial risks and uncertainties for purposes of the safe harbor provided by the Private Securities Litigation Reform Act of 1995. All statements, other than statements of historical facts, included in
Slide 3: Synthetic Biotic Medicines: A Novel Class of Living Medicines
Synthetic Biotic Medicines: A Novel Class of Living Medicines Synthetic Biology + Bacteria = Synthetic Biotic Medicine Therapeutic delivered locally to treat systemic diseases SyntheticEngineered bacteriaWith designed genetic circuitsTo degrade metabolites that induce disease or synthesize substance
Slide 4: Synthetic Biotic Platform Breadth and Potential
Synthetic Biotic Platform Breadth and Potential: Initial Clinical Focus on Orphan Metabolic Diseases Immuno-Oncology (IO) Synthetic Biotic Platform Internal Pipeline Focus Immunomodulation Inflammatory Bowel DiseaseOn-going Partnership Other Inflammation and Immunology Metabolic Diseases Rare Diseas
Slide 5: Rare Diseases: Hyperammonemia and Phenylketonuria Programs in Clinical Trials in 2018
Probiotic bacteria:E. coli Nissle Correct the deficiency Ammonia ✓ Phenylalanine ✓ Synthetic Biotic Probiotic bacteria:E. coli Nissle Conversion of Toxic Ammonia into Beneficial Arginine PROGRAM 1: SYNB1020Hyperammonemia (UCD and HE) Degradation of Toxic Phenylalanine to Non-Toxic Amino Acid Metabol
Slide 6: Synthetic Biotic Platform Breadth and Potential: Current Pipeline
Synthetic Biotic Platform Breadth and Potential:Current Pipeline Inborn Errors of MetabolismMetabolic DiseaseImmunomodulation Immuno Oncology 1: STING A/Kyn Consumer Lead Discovery Lead Optimization IND-Enabling Studies Phase I Phase II Hyperammonemia -Urea Cycle Disorder SYNB1020 Phenylketonuria SY
Slide 7: SYNB1020 for Hyperammonemia: UCD and HE
SYNB1020 for Hyperammonemia Indications: Urea Cycle Disorders (UCD) and Hepatic Encephalopathy (HE) Both diseases are characterized by systemic ammonia accumulation Break in cycle / inefficient cycle Ammonia x Ammoniabuild up (toxic levels) Urea cycle ! Urea(removed from the body normally) Urea cycl
Slide 8: SYNB1020 Mechanism of Action
SYNB1020 Mechanism of Action:Conversion of Toxic Ammonia into Beneficial Arginine for the Treatment of UCD and HE Urea cycle Ammonia/ NH4Cl Urea Under normal conditions, urea cycle metabolizes ammonia into ureaWhere ammonia is not efficiently metabolized via urea cycle, SYNB1020 provides an alternat
Slide 9: SYNB1020 Preclinical Characterization
SYNB1020 Preclinical Characterization:Potent and Efficacious Ammonia Reduction and Improved Survival Potency in vitro Arginine as biomarker of strain activity Dose dependent survival and ammonia lowering in vivo 300 400 200 500 0 100 Vehicle 1010 HI 5x109 1x1010 1x109 Vehicle 1010 HI 5x109 1x1010 1x
Slide 10: SYNB1020 Biomarkers of Mechanism
SYNB1020 Biomarkers of Mechanism:Increase of Plasma and Urinary Biomarkers and Improvement in Urea Cycle in Mice Plasma L-arginine Plasma L-citrulline 0.000 0.010 0.020 0.030 SYNB1020 Vehicle [L-Arg] (mM) 6 hours SYNB1020 Vehicle 6 hours [L-Cit] (mM) Urinary urea Urinary NOx (nitrite + nitrate) SYNB
Slide 11: SYNB1020 Biomarkers in Phase SAD / MAD Study
Urinary nitrate SYNB1020 Biomarkers in Phase 1 SAD / MAD Study:Significant Dose-Dependent Effect on Plasma and Urinary 15Nitrate 500 1,500 0 1,000 Placebo 6x109 6x1011 1.5x1012 15N-nitrate amount excreted in urine CFB(MPE*mL) Total daily CFU x 14 days Plasma nitrate 6 8 4 -4 -2 2 0 Placebo 6x109 6x1
Slide 12: SYNB1020 Biomarkers in Phase SAD / MAD Study: Summary of Biomarker Strategy
SYNB1020 Biomarkers in Phase 1 SAD / MAD Study:Summary of Biomarker Strategy Healthy humans have a robust urea cycleRapidly convert excess ammonia into ureaMaintain consistent ammonia levelsIn the Phase 1 study of healthy volunteers, an oral dose of 15NH4CL was followed by blood and urine sampling o
Slide 13: Phase 1 SAD / MAD Study: Safe & Well Tolerated with Fast Clearance
SYNB1020 clearance within 2 weeks following completion of dosing Dose dependent steady-state SYNB1020 qPCR SYNB1020 Phase 1 SAD / MAD Study:Safe & Well Tolerated with Dose-dependent Exposure Relationship and Fast Clearance Steady-state qPCR copy number increases with increasing SYNB1020 dose Followi
Slide 14: SYNB1020 Clinical Development: Next Steps
2018 2019 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 HE Ph 1b / 2a UCD Ph 1b / 2a Program Urea CycleDisorder Hepatic Encephalo-pathy SYNB1020 Clinical Development: Next Steps: HE and UCD Patient Studies in 2018 Urea Cycle DisordersDemonstrate safety/tolerability in adults with late onset UCDInitiate Phase 1b/2a in H2
Slide 15: SYNB1618 for Phenylketonuria (PKU)
SYNB1618 for Phenylketonuria (PKU):Facilitating Normalization of Plasma Phe Levels Rare Inherited amino acid metabolism disorder Causes build up of amino acid phenylalanine (Phe) in the bodyPhenylalanine is found in all proteinsDiagnosed: 16,500 in US, similar in EU5If left untreated, symptoms inclu
Slide 16: SYNB1618 Mechanism of Action
SYNB1618 Mechanism of Action:Designed to Convert Toxic Phenylalanine to Trans-cinnamic Acid Phe PKU Healthy Amino acids fromdietary proteins [Absorption andRecirculation] Phenylalanine Hydroxylase (PAH): converts Phe into Tyrosine Impaired PAH Tyrosine ! Phenylalanine Hippuric acid Normalized levels
Slide 17: SYNB1618 Preclinical Characterization in Mice
SYNB1618 Preclinical Characterization in Mice: Efficient Phe Degradation and Hippuric Acid Excretion Dose-responsive urinary hippuric acid production in Pahenu2 Reduced plasma Phe in Pahenu2 mice 3.13x109 6.25x109 1.25x1010 2.5x1010 5x1010 1x1011 1x1011 Urinary HA / cage (mmol) SYNB1618 Nissle 1.0 0
Slide 18: SYNB1618 Preclinical Characterization in Healthy NHPs
SYNB1618 Preclinical Characterization in Healthy NHPs: Proof of Mechanism - Metabolizes Phe Whether Administered Orally or Systemically Phe (oral administration) metabolism with a Synthetic Biotic medicine 13C Phe (systemically administered) metabolism to 13C HA with Synthetic Biotic medicine 0.10 0
Slide 19: SYNB1618 in NHPs: Phe Metabolism is Dose Responsive
300 100 200 0 SYNB1618 Preclinical Characterization in Healthy NHPs:Phe Metabolism is Dose Responsive Dose dependent excretion of urinary HA 0 3x109 1.1x1010 2.3x1010 4.5x1010 9x1010 1.8x1011 3.6x1011 7.2x1011 HA (mmoles) Dose dependent conversion of Phe to plasma TCA 0 3x109 1.1x1010 2.3x1010 4.5x1
Slide 20: SYNB1618 in NHPs: Phe Metabolism is Clinically Relevant
SYNB1618 Preclinical Characterization in Healthy NHPs:Phe Metabolism is Clinically Relevant PKU patients: restricted to <10g protein/dayExtrapolation from highest dose in NHPs: Supports a minimum of 25g of dietary protein intake in humans~50% of daily recommended protein intake (US RDA) or 2.5x incr
Slide 21: SYNB1618 in the Clinic: Phase SAD/MAD
SYNB1618 in the Clinic:Phase 1 SAD/MAD in Healthy Volunteers with Patient Cohort 2017 2018 2019 Q3 Q4 Q1 Q2 Q3 Q4 Q1 Q2 Pre-clinical / IND enabling studies SAD/MAD Patient cohort SAD / MAD HV Goal: assess safety, tolerability and kinetics in healthy volunteers across a range of dosesIncludes cohort
Slide 22: SYNB1020 and SYNB1618: What We Have Learned
SYNB1020 and SYNB1618:What We Have Learned Preclinical Clinical Regulatory Manufacturing Successful Regulatory interactions: Established a development path: requirements for preclinical and clinical testing and manufacturing of a live biotherapeutic Completed Phase I study in 52 healthy volunteers f
Slide 23: Manufacturing: Drug Substance and Drug Product
Strain engineeringFast - >40 in 3 yearsSwitch technology enables productive biomass In vitro testingSmall scale manufacture- ambr® 15In-house testing of:Strength – CFUsPotency – micro well plate assays Discovery and Preclinical Drug Substance Clinical suppliesStandard process for consistent biomass
Slide 24: Synthetic Biotic Platform: Bringing Rational Drug Development to the Microbiome
GMP manufacturing:Single strainReproducible yieldFormulation & deliveryControl switchesPortfolio applicability Synlogic Synthetic Biotic Platform: Bringing Rational Drug Development to the Microbiome Rational design:Synthetic biology tools appliedEngineer potencyExceed endogenous bacterial activity
Slide 25: Applicability Beyond Rare Disease Across Multiple Pathways
Synthetic Biotic Medicines: Applicability Beyond Rare Disease Across Multiple Pathways Short Chain Fatty Acids: ButyrateAcetatePropionate Proteins and PeptidesIL2, IL12, IL15, IL22,IL10IFN, TNF, CXCL10, CD40L, hyaluronidaseGLP1, GLP2 Amino Acid MetabolismBranched Chain AAsTrp, Kyn, indoles, Serotoni
Slide 26: SYN-MSUD for Maple Syrup Urine Disease
SYN-MSUD for Maple Syrup Urine Disease (MSUD):Degradation of toxic branched-chain amino acids Branched-chain amino acids (BCAA) Valine Leucine Isoleucine BCAA aminotransferase Branched-chain ketoacids Branched-chain Acetyl-CoAs Mutation in branched-chain a-keto acid dehydrogenase complex (BCKD) ATP
Slide 27: SYN-MSUD In Vivo: Lowers Plasma and Brain Leu Levels
SYN-MSUD In Vivo: Lowers Plasma and Brain Leu Levels Plasma Leu significantly reduced on Day 3Trend for Leu lowering in the brain Plasma Brain Protective effect on iMSUD animals fed high-protein chow
Slide 28: Engineered Probiotics to Modulate Cross-talk between the Gut and the Liver or Brain
Metabolite production, consumption, transformation Neurotransmitter or hormone production/consumption,Toxin consumption,Neuroprotectant production Bianconi et al., Atlas of Human Biology 2013Sender et al, PLoS Biology 2016 Engineered Probiotics to Modulate Cross-talk between the Gut and the Liver or
Slide 29: Synlogic Mission: Bringing Minimal Therapeutic Genomes to Oncology
HORIZON 3 HORIZON 2 Test simple synthetic biology concepts in the local tumor microenvironment Harness microbiome metabolomics to widen response to cancer immunotherapies Rationally build full minimal genomes solely designed for wide therapeutic use in cancer HORIZON 1 Synlogic Mission: To Re-define
Slide 30: Synlogic Vision for Immuno-Oncology
Synlogic Vision for Immuno-Oncology: One Drug, 2 Mechanistic Modules to Turn Cold Tumors to Hot, Driving High Response Rates and Abscopal Effect STING Agonist KYNConsumer SYNB0828: Lead IO Program Immune Initiator: Antigen Release, Activation & Priming Immune Sustainer: Immune Augmentation & T Cell
Slide 31: Synlogic Development Pipeline: Programs' Timelines Summary
Synlogic Development Pipeline:Programs’ Timelines Summary 2018 2019 Q1 Q2 Q3 Q4 Q1 Q2 Q3 Q4 SAD/MAD Patient Cohort HE Ph 1b / 2a IND enabling studies IND enabling studies SAD/MAD HV UCD Ph 1b / 2a PKU Program IO UCD MSUD HE
Slide 32: Significant Delivery in 2017, Primed to Deliver in 2018
Synlogic:Significant Delivery in 2017 …. Primed to Deliver in 2018 2017 Accomplishments 2018 Goals Significant pipeline progress: SYNB1020: UCD / HEPhase 1 completionFast track designationSYNB1618: PKUOrphan statusIND on track for Q1 ’18Corporate:Public listing on NASDAQ1st milestone in AbbVie colla
Slide 33: Synlogic Overview
Synlogic Overview NovelTherapeuticClass Dominant Synthetic Biotic IP PortfolioAs of Jan 2018 Strong Balance Sheet Leader of therapeutic synthetic biology, genetically reprogram probiotics for transformative impact on disease treatmentSimple, robust and rapid process for the discovery, development an
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Slide 35: Synlogic Management Team
Synlogic Management Team: From Funding of Platform to Clinic in Less than Three Years JC Gutierrez-Ramos, CEO Group SVP Biotherapeutics, PfizerSVP, Head Immunoinflammation Center for Drug Discovery, GSKCSO & Site Head, Amgen Mountain View Dean Falb, CTOEntrepreneur in Residence, Atlas VentureVP, R&D
Slide 36: SYNB1020 for Treatment of Liver Disease: Potential Mechanisms of Action
SYNB1020 for Treatment of Liver Disease:Potential Mechanisms of Action Engineered probiotic bacteria have the potential beyond ammonia control in hepatic encephalopathy Hepatic EncephalopathyPathogenesis 800 400 0 1,200 HealthyControl SYN1020 Vehicle SYN1020 Heat inactivated SYN1020 Heat inactivated
Slide 37: SYNB1020 for Hyperammonemia: Strong Preclinical Package
Animal Data Human Data Potency In vitroAmmonia consumptionArginine production: nitrate precursor Exposure Survival past stomach and small intestine:In mouse models of disease In simulated human gut (Prodigest) Dose exposure relationshipFunctional activity following transit through the gut Biomarker
Slide 38: SYNB1020 Phase 1 SAD / MAD Study: Safe and Well-Tolerated
Cohort 2: 2 x 1011 TID Cohort 1: 2 x 109 TID Cohort 3: 5 x 1011 TID 1x1012 CFU x 3 / day Days 2x1010 CFU 5x1011 CFU x 3 / day 2x109 CFU / day 2x1011 CFU 2x1012 CFU x 3 / day 2x1012 CFU A randomized, double-blind, placebo-controlled study to assess the safety, tolerability, and pharmacodynamics of SY
Slide 39: SYNB1020: Toxicology Package and Regulatory Path
SYNB1020: Toxicology Package and Regulatory Path Orphan Drug Designation (UCD, PKU)Fast Track Designation (UCD)Feedback from FDA Office of Vaccines Research and Review (CBER)No Recombinant DNA Advisory Committee (RAC) requiredLowering of blood ammonia level is an approvable end-point (UCD) Preclinic
Slide 40: CMO Manufacture: From Flask to Industrial Fermenter
CMO Manufacture - From Flask to Industrial Fermenter: Well-Controlled Process at 150L Successful Scale-up to Biomass for Clinical Scale Number of doses at 1e12 CFU 10000 1000 100 10 Shake flask – 250 mL Shake flask – 500 mL Shake flask – 1 L Bench fermenter – 5 L Pilot fermenter – 25 L Pilot ferment
Slide 41: SYNB1618 PKU Design and Preclinical Characterization
SYNB1618 PKU Design and Preclinical Characterization:Efficient Phe Degradation In Vitro and In Vivo With pheP Transporter Without pheP Transporter 20 10 10 0 5 Phe Degradation Rate(μmoles/h/10e9cells) IntegrationSite PAL copyNumber IntegrationSite PAL copyNumber pheP copyNumber LAAD +3XPAL + pheP+ L
Slide 42: SYN1618 Preclinical Characterization: Casein Study in NHPs
SYN1618 Preclinical Characterization:Casein Study in NHPs NHP challenge studies:Oral D5-PheSQ D5-PheOral dipeptides and tripeptides with D5-PheCasein containing D5-Phe Plasma D5-Phe Plasma D5-TCA Plasma D5-HA Phenylalanine Probiotic bacteria: E. Coli Nissle Synthetic Genetic Circuit Phenylalanine t-
Slide 43: Synthetic Biotic Medicines: Designed for Clinical Performance
Synthetic Biotic Medicines: Designed for Clinical Performance BUILT TO TRANSLATE ACTIVITY & DOSE In silico design, pathway modelingEnzyme selection, optimization10+ Switches for GI sensingPromoters for signal optimizationSystems profiling of cell metabolism PROGRAMMED TO SENSE AND RESPOND ENGINEERED
Slide 44: Synthetic Biotic Platform: Rational Drug Discovery and Development
Synthetic Biotic Platform: Rational Drug Discovery and Development Rapid Lead Generation Predictable and Controlled Scale Up for Drug Substance Rational and Efficient Lead Optimization Drug Product Feasibility PK/PD Based on Unique Biomarkers Regulatory Path Dose Response Safety and ToxicologyResemb
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